Long-Term Transcutaneous Stimulation and Essential Tremor: A PET Study

Hypothesis:

The primary research question is whether customized patterned transcutaneous afferent
electrical stimulation to the median and radial nerves via the Cala TWO wrist-band device
significantly reduces hand tremors in individuals diagnosed with essential tremor that have
been approved as candidates for deep brain stimulation (DBS) surgery. A second research
question is whether three months of treatment with the Cala TWO device leads to significant
changes in regional brain metabolism that is associated with therapeutic efficacy.

Aims, purpose, or objectives:

Aim 1: Determine the clinical efficacy of the Cala TWO device to transiently reduce hand
tremors in the treated hand of subjects with essential tremor (n=20) over a three month
treatment period prior to their undergoing DBS surgery for treatment of essential tremor at
Mayo Clinic.

Aim 2: Compare regional brain metabolism between baseline, after acute stimulation with the
Cala TWO device, and at exit 3 months after therapeutic treatment with the Cala TWO device.
18Ffluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computerized Tomography (CT)
scans will be applied in a subset (n=10) of essential tremor subjects to evaluate changes in
brain tissue metabolic activity corresponding to regional glucose uptake.

Aim 1 Methods:

Design of the Cala TWO device Study: Subjects will be recruited exclusively from adult
essential tremor (ET) patients that have been approved by Mayo Clinic Deep Brain Stimulation
Group (comprised of neurosurgeons, neurologists, psychiatrists, and radiologists) to undergo
deep brain stimulation surgery at Mayo Clinic - Rochester for the treatment of ET. As such,
subjects that consent to this study are expected to readily meet the pre-specified inclusion
criteria noted below for participation in the study.

Regardless, all subjects will be pre-screened against the inclusion/exclusion criteria
through face-to-face interviews. Additionally, baseline function and tremor severity will be
collected in the first visit phase of the study. Subjects already taking medications for ET
will be permitted these medications during the study with no changes in medication type or
dosage.

All subjects will be fitted with a Cala TWO device based on the subject's wrist circumference
(small, medium, or large) and stimulation hand (right or left) at the beginning of the study
visit. The stimulation hand will be the hand with more severe tremor (or the dominant hand if
both hands had equal tremor severity) as determined by the TETRAS task completed during the
baseline evaluation and pre-surgery clinical evaluation by the Mayo Clinic DBS group. Once
the Cala TWO device has been fitted to the subject's hand a frequency calibration procedure
will be conducted in which the subject's tremor frequency will be determined while the
subject performs a forward postural hold task. This frequency will then be incorporated into
the therapeutic stimulation waveform.

Stimulation will consist of a series of charge balanced biphasic pulses delivered at a
frequency of 150 Hz, 300 µs pulse width, and 50 µs inter-pulse period. The stimulation will
be alternated between the median and radial nerve at a frequency equal to tremor frequency
(i.e. for a measured 5 Hz tremor frequency, stimulation will be applied over the median nerve
for 200 msec, then alternated to be applied over the radial nerve for 200 msec). To determine
the stimulation amplitude, the site study neurologist will increase the stimulation level by
0.25 mA steps until the subject reports sensation of the stimulus in areas in the hand or
finger area. Final stimulation amplitude will be chosen to be the highest level of
stimulation below muscle contraction that the subject finds comfortable (mean: 5.4 mA +/-
2.9). Once the maximum tolerable stimulation level has been identified, subjects will receive
stimulation at that level during the 40-minute stimulation session. Adverse events will be
collected before, during, and after each stimulation session. Subjects will then receive
device training and instructions by on-site study personnel for conducting daily home
stimulation sessions.

Power Statement: This is a pilot study with a unique subject cohort.

Data Analysis Plan:

An analysis of covariance (ANCOVA) model will be used to assess the statistical significance
of the difference in the mean change in tremor before and after treatment.

Efficacy will be measured as the change in the TETRAS scale measure of upper limb tremor
following stimulation compared with pre-stimulation. Additional analyses will include the
Bain & Findley 4-point scale assessment of typical Activities of Daily Living (ADL) and the
Patient Global Impression - Severity (PGI-S) 7-point scale of the subjects' personal
assessment of how much their tremor level improved or worsened relative to their baseline
state prior to the stimulation session.

The primary safety endpoint will be an analysis of adverse events types and rates for all
enrolled subjects, where the adverse event rate will be calculated as the percentage of total
subjects with an adverse event.

Aim 2 Methods:

The investigators propose to recruit subjects (n=10; age 21-70) from the population of
subjects that have enrolled in the Cala TWO device which is a 3-month treatment duration
study with the Cala TWO device prior to subject's scheduled deep brain stimulation surgery.
This optional component of this study will perform three standard PET/CT sessions on these
subjects at the Mayo Clinic Molecular Research Imaging Facility to evaluate changes in brain
tissue metabolic activity as a result of 3 months treatment with the device. The advanced
clinical PET scanner PET/CT will be used in this study, equipped with digital silicon
photomultiplier detectors.

First session: Takes place upon a subject's entry into the Cala TWO study (start of month 1)
and prior to any treatment with the Cala device.

Second session: Takes place the following day after a 40 minute treatment period with the
Cala device.

Third session: Takes place at the end of the third month of use of the device.

Minimizing the Radiation Risk: By using an advanced clinical PET scanner, equipped with
digital silicon photomultiplier detectors, the investigators will be using a reduced
intravenous delivered dose of FDG (8 mCi).

Attenuation Correction Scans: For PET/CT, a low-dose CT fusion skull scan (~1min) will be
acquired for attenuation correction and anatomical co-registration.

Step-by-Step Schedule:

The FDG scan slots are available at 7:30am, 8:00am, 8:30am, and 10:30am. Participants with
head tremor would present problems in obtaining quality scans. If this is the case, a head
secure procedure will be included.

1. A 4 hour fast is required prior to FDG injection. Patients are given instructions to
remain well-hydrated and have a low carbohydrate diet 18 hours before their appointment.

2. No significant alcohol or caffeine consumption and no usage of the Cala TWO device
within 8 hours of a PET session.

3. Blood sugar level will be checked by a finger-poke blood test. Fasting blood glucose
should be under 200 mg/dL.

4. Women of child-bearing potential will go through a urine-pregnancy test, unless there is
proof of negative results within 48 hours before the exam.

5. 8 mCi FDG injection through IV and rest at the uptake room (eyes open in a dimly lit
room).

6. At 30 minute uptake time, conduct a PET/CT scan for a 15 min. A 1 min CT fusion skull
image will be acquired for attenuation correction and anatomical co-registration.

Power Statement: This is a pilot study with a unique subject cohort.

Data Analysis Plan:

CortexID (GE Medical Systems, LLC) and MIMneuro (MIM Software Inc.) will be used to confirm
quality control of the PET image. Additional quantitative analysis of PET images will be
conducted using SPM, FSL, and Analyze. CortexID. This quantification procedure uses a
patient-specific FDG z-score map derived by comparing the surface projection map (z-SPM) with
an age- and sex-matched normal control FDG database.

Subject population (children, adults, groups): Adults approved for DBS surgery at Mayo
Clinic for treatment of essential tremor

Inclusion Criteria:

- Prospective subjects must meet all of the following criteria to be eligible for study
participation:

- Must be greater than or equal to 21 years of age. Must be approved for DBS surgery at
Mayo Clinic for treatment of essential tremor.

- Competent and willing to provide signed, informed consent to participate in the study.

- Stable dose of tremor medications, if applicable, for 30 days prior to study entry.

- Stable dose of antidepressant medications, if applicable, for 90 days prior to study
entry.

- Willing to comply with study protocol requirements including: remaining on a stable
dosage of tremor and antidepressant medications, if applicable, during the duration of
the study; no significant alcohol or caffeine consumption within 8 hours of study
visits; no usage of the Cala TWO device within 8 hours of study visits.

Exclusion Criteria:

- Prospective subjects that meet any of the following criteria are not eligible for
enrollment in this study:

- Moderate to severe ethanol dependence as defined by the criteria outlined in the DSM-5
(score of 4 or higher).

- Implanted electrical medical device, such as a pacemaker, defibrillator, or deep brain
stimulator.

- Previous thalamotomy procedure, including stereotactic thalamotomy, gamma knife
radiosurgical thalamotomy, and focused ultrasound for the treatment of tremor.

- Suspected or diagnosed epilepsy or other seizure disorder. Swollen, infected, inflamed
areas, or skin eruptions, open wounds, or cancerous lesions of skin at stimulation
site (wrist).

- Peripheral neuropathy affecting the tested upper extremity. Presence of any other
neurodegenerative disease like Parkinson plus syndromes suspected on neurological
examination. These include: multisystem atrophy, progressive supranuclear palsy,
dementia with Lewy bodies, and Alzheimer's disease.

- Anyone suspected to have the diagnosis of idiopathic Parkinson's disease (PD). This
includes excluding anyone with the presence of parkinsonian features including
bradykinesia rigidity, or postural instability. Subjects that exhibit only mild
resting tremor but no other symptoms or signs of PD may be included.

- Botulinum toxin injection for hand tremor within 6 months prior to study enrollment.

- Are participating or have participated in another interventional clinical trial in the
last 30 days which may confound the results of this study, unless approved by the
Principal Investigator.

- Significant alcohol or caffeine consumption within 8 hours of study enrollment, which
may confound the results of the study, where significant caffeine is considered more
than 95 mg (equivalent to a cup of coffee), and significant alcohol is considered more
than 14 g (equivalent to 5 oz of wine, 12 oz of beer, or 1.5 oz of distilled spirits).

- Subjects unable to communicate with the investigator and staff. Any health condition
that in the investigator's opinion should preclude participation in this study.

- Pregnancy or anticipated pregnancy during the course of the study.